Immunoglobulin E (IgE) plays a central role in mediating type I hypersensitivity reactions that are responsible for causing allergic diseases, including allergic asthma, allergic rhinitis, atopic dermatitis, peanut allergy, latex allergy, and others. Allergic reactions are the responses of the immune system toward harmless environmental substances, such as dust mites, tree and grass pollens, certain food and drugs, and bee and fire ant bites. In such reactions, the binding of an allergen to IgE on the surface of basophils and mast cells causes the cross-linking of IgE and the aggregation of the underlying receptors of IgE.Fc, the type I IgE.Fc receptors, or FcεRI. This receptor aggregation subsequently activates the signaling pathway leading to the exocytosis of granules and the release of pharmacologic mediators, such as histamine, leukotrienes, tryptase, cytokines and chemokines. The release of those mediators from mast cells and basophils causes the various pathological manifestations of allergy.
Anti-IgE antibodies binding to free IgE in the blood and in interstitial fluid and to mIgE on B cells, but not to IgE bound by FcεRI on basophils and mast cells, such as omalizumab and TNX-901, have been developed for treating IgE-mediated allergic diseases. These antibodies bind to IgE with high affinity at a site in the CH3 domain of Fc that overlaps with the binding site of FcεRI. Hence, the anticipated therapeutic effects of these antibodies are based on the binding of the antibodies to free IgE and to mIgE on B lymphoblasts and on memory B cells, which leads to the reduction of overall free IgE level in blood and interstitial fluid.
The clinical development of omalizumab (trade name Xolair) has shown additional multiple pharmacologic effects in attenuating type I hypersensitivity in various allergic indications. The binding of anti-IgE to free IgE further prevents IgE binding to FcεRI on the surface of basophils and mast cells. As the FcεRI unoccupied by IgE is unstable and subsequently internalized and degraded, the depletion of free IgE with anti-IgE binding also gradually down-regulates FcεRI on basophils and mast cells. Evidence for other effects of the antibody therapy has been found, including the neutralization of cytokinergic activities, the attenuation of overall inflammatory activity, and possibly the sweeping of allergens through the accumulation of IgE-anti-IgE immune complexes.
CεmX is a 52-amino acid segment located between the CH4 domain and the C-terminal membrane-anchoring segment of human membrane-bound ε chain (mε). It has been shown that in most human subjects studied, the mε without CεmX (mεS) accounts for minute proportions, whereas mε chain with CεmX (mεL) is dominantly expressed. The mRNAs for ε chain of free, secreted IgE and for mεS and mεL of mIgE are all derived from alternative splicing of the ε RNA transcript. The amino acid and nucleotide sequences of CεmX are unique in the entire protein and DNA databases. Therefore, CεmX provides a unique antigenic site for targeting mIgE and the mIgE-expressing B cells.
Anti-IgE antibodies binding to the CεmX (also known as the M1′ region or M1′ peptide), which exists on human mIgE for the targeting of mIgE-expressing B lymphocytes, have also been developed. See, e.g., Chen et al., J. Immunol., 184: 1748-1756, 2010; U.S. Pat. No. 8,071,097; and WO2010/097012.
It is of great interest to identify new antigenic epitopes within the CεmX domain and develop new therapeutic antibodies binding to such antigenic epitopes.